N-isoquinolylalkanoyl-n-arylamines



United States Patent 3,483,206 N-ISOQUINOLYLALKANOYL-N-ARYLAMINESLincoln Harvey Werner, Summit, N.J., assiguor to Crba Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Continuation-impart ofapplication Ser. No. 525,312, Feb. 7, 1966. This application Dec. 15,1967, Ser. No. 690,761

Int. Cl. C076 35/36; A61k 21/00 US. Cl. 260-286 2 Claims ABSTRACT OF THEDISCLOSURE N-(3,4-dihydroor 1,2,3,4 tetrahydro 2 isoquinolylalkyl or-alkanoyl)-N-arylamines, e.g. those of the formula l X Ar Ar=aryl;N-oxides, quaternaries and salts thereof exhibit antileptospire effects.

CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-partof application Ser. No. 525,312 filed Feb. 7, 1966.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new N-(3,4-dihydroorl,2,3,4-tetrahydro-2-isoquinolyl-alkyl or -alkanoy1) N arylamines,particularly such of the Formula I DESCRIPTION OF THE PREFERREDEMBODIMENTS The 1,2-phenylene radical Ph is unsubstituted or substitutedby one or more than one of the same or different substituents attachedto any of the positions available for substitution. Such substituentsare, for example, lower alkyl, such as methyl, ethyl, nor i-propyl, n-,i-, sec. or tert.-butyl, etherified or esterified hydroxy or mercapto,for example, lower alkoxy, alkylenedioxy or alkylmercapto, such asmethoxy, ethoxy, nor ipropoxy or n-butoxy, methylenedioxy, 1,1- or 1,2ethylenedioxy, methylor ethylmercapto, or halogen, such as fluoro,chloro or bromo, trifluoromethyl, nitro or amino, such as di-loweralkylamino, e.g. dimethylamino or diethylamino. The term lower referredto above or hereinafter in connection with organic radicals or componudsrespectively, defines such with up to 7, preferably up to 4, carbonatoms.

A lower alkyl radical R and/or R is, for example,

one of those mentioned above, but also straight or branched pentyl,hexyl or heptyl bound in any position. R preferably stands for alkylwith up to 4 carbon atoms and R for hydrogen, but also for loweralkanoyl, such as acetyl, propionyl, butyryl or pivalyl.

Thearyl radical R is, for example, carbocyclic or heterocyclic monoorbicyclic aryl, such as phenyl, naphthyl, tienyl, furyl, pyridyl,quinolyl or isoquinolyl. It preferably stands for unsubstituted orsubstituted phenyl, which latter may contain one or more than one of thesame or different substituents, such as those mentioned for thephenylene radical Ph.

The lower alkylene group alk is preferably methylene, but also 1,1- or1,2-ethylene, 1,1-, 1,2-, 2,2- or 1,3-propylene, 1,1-, 1,2-, 2,2-, 1,3-or 1,4-butylene, 2-methyl1,3- propylene, 2,3-, 2,4- or 1,5-pentylene1,4-hexylene or 2,6- heptylene. The alkylene group alk is preferably1,2-ethylene but also 1,2-propylene, 1,2- or 2,3-butylene, 1,2- or2,3-pentylene, 1,2-, 2,3- or 3,4-hexylene or 3,4-heptylene.

The componuds of the invention exhibit valuable pharmacologicalproperties. Apart from some adrenolytic effects, they show primarily aspecific effect against protozoa, particularly leptospira, such as Lept.pomona, canicola 0r icterohemorrhagiae, as can be demonstrated in vitroand in animal using, for example, mammals, such as dogs or hamsters astest objects. Besides their above-mentioned utility, the compounds ofthe invention are also useful intermediates for the preparation of othervaluable products, preferably of pharmacologically active compounds.

Particularly useful are compounds of the Formula I, in which Ph is1,2-phenylene, (lower alkyl)-1,2-phenylene, (lower alkoxy)-1,2pheny1ene,(halogeno)-1,2-phenylene or (trifiuoromethyl)-1,2-phenylene, each of Rand R is hydrogen or lower alkyl, R is the radical in which each of R Rand R is hydrogen, lower alkyl, l-ower alkoxy, halogeno ortrifluoromethyl, X is 0x0 or thio, alk is methylene, 1,2-ethylene or1,3-propylene and alk is 1,2-ethylene, their acid addition salts and1,2-dehydro-quaternaries.

Compounds that are especially valuable are those of the Formula II inwhich R, is alkyl with up to 4 carbon atoms, and R is phenyl ortrichloro-phenyl, their therapeutically acceptable acid addition saltsand quaternary 1,2-dehydro halides which, when given to hamsterssubcutaneously at doses between about 1 and 50 mg./kg., or orallybetween about 10 and mg./kg., show outstanding antileptospira activity,especially against L. pomo nw.

The dispersion of leptospirosis is related to specific environmentalconditions, particularly those which bring animal carriers, water andmud together. Animal carriers often excrete a profusion of leptospiresin the urine-up to million per ml. If the urine is excreted into wateror mud which is neutral or slightly alkaline, the leptospires maysurvive for weeks. Susceptible animals entering this environment-areexposed to the agent and may develop infection, varying from aninapparent response to an acute fulminating fatal disease. Theleptospires usually enter the body through the mucous membranes of theconjunctivae, nose or mouth, or the broken or macerated skin.Leptospirosis now constitutes a major problem in cattle and a problem ofundetermined size in swine. In some areas sheep, goats, and horsesbecome infected too.

The compounds of the invention are prepared by methods in themselvesknown, for example, the process con sists in:

(a) reacting a Z-unsubstituted 3,4-dihydroor 1,2,33,4-tetrahydro-isoquinoline with a reactive ester of an N-hydroxyalkyl or-alkanoyl-N-arylamine or a corresponding epoxide or (b) reacting areactive derivative of a (3,4-.dihydroor 1,2,3,4 tetrahydro 2isoquinolyl) alkanol or -alka noic acid with a primary or secondaryarylamine or (c) reducing in an N (3,4 dihydroor 1,2,3,4 tetrahydro 2isoquinolyl alkyl or -alkanoyl) N arylamine containing adjacent to thering-nitrogen atom at least one carbonyl group, said group to themethylene group or (d) condensing a reactive ester of al-(B-hydroxyalkyl) 2 (a hydroxyor oxo alkyl) benzene with a primary Naminoalkylor -alkanoyl N arylamine or (e) ring closing a 1 (ahydroxyalkyl) 2 (B- arylaminoor arylcarbamylalkylamino alkyl) benzene or1 (,3 hydroxyalkyl) 2 (a arylaminoor arylcarbamylamino-al'kyl)-benzene,or a reactive ester thereof and, if desired, converting a resultingcompound into another compound of the invention.

A reactive ester of the alcohol mentioned under items (a), (b), (d) and(e) is, for example, that of a hydrohalic or sulfonic acid, such ashydrochloric, hydrobromic, methane-, ethane-, benzeneorp-toluenesulfonic acid. A reactive derivative of the alkanoic acid usedin reaction (b) is, for example, a halide, e.g. chloride or bromide, ananhydride, e.g. the adducts of ketenes, an ester, such as a lower alkylor aralkyl ester or the N-unsubstituted amide. Said reactive esters areadvantageously used in the presence of basic condensing agents, such asalkali or alkaline earth metal carbonates or bicarbonates or tertiarynitrogen bases, such as triethylamine, N,N-dimethyl-aniline or pyridine.Epoxides may advantageously be reacted in the presence of small amountsof water and/ or acids, e.g. hydrochloric acid, which catalysts are alsouseful in the amidation of the acid anhydrides, esters and amides.

The reduction according to item (c) is carried out, for example, withthe use of complex light metal hydricles, such as lithium aluminumhydride, or with hydrogen, e.g. under electrolytic conditions.

The condensation mentioned under item (d) may be carried out in one ortwo steps, in the latter instance compounds mentioned under item (e) areobtained. In case they are reactive esters, the reaction conditions areanalogous to those mentioned above. Free hydroxyalkyl compounds areadvantageously ring-closed in the presence of dehydrating agents, suchas sulfuric or polyphosphoric acid or carbodiimides.

The compounds of the invention so obtained may be converted into eachother by methods in themselves known. Thus, for example, a compoundunsaturated in the 1,2-positions may be hydrogenated with catalyticallyactivated or nascent hydrogen, such as hydrogen in the presence ofplatinum, palladium or nickel catalysts, or hydrogen generated by analkali metal in an alcohol by electrolysis or with the use of complexlight metal hydrides such as sodium borohydride. Amides or thioamidesobtained may be reduced according to the method shown under item (c).Secondary amines or monosubstituted amides may be reacted with reactiveesters of lower alkanols, regular amides may be converted intothioamides, for example, by reaction with a phosphorus sulfide, andsecondary amines acylated with reactive derivatives of lower alkanoicacids, e.g. those mentioned above.

The N-oxides of the invention are obtained, for example, by reacting thefree bases with hydrogen peroxide or a peracid, e.g. peracetic,perbenzoic or nionoperphthalic 4 acid. Quaternaries are formed byreaction of the bases with a reactive ester of an alcohol, preferablythat of a lower alkanol with a hydrohalic acid.

The above mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/ or inert atmospheres, at low temperatures, room temperatureor elevated temperatures, at atmospheric or superatmospheric pressure.

The compounds of the invention are obtained in the free form or in theform of their salts, depending on the conditions under which the processis carried out; the salts are also included in the present invention.Salts that are obtained can be converted into the free bases in knownmanner, for example, with alkalis or ion exchangers. Free bases that areobtained can be converted into salts by reaction with organic orinorganic acids, especially those that are suitable for the formation oftherapeutically useful salts. Such acids are, for example, hydrohalicacids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric,nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromaticor heterocyclic carboxylic or sulfonic acids, for example, formic,acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic,aminobenzoic, anthranilic, hydroxybenzoic, salicylic, aminosalicylie,embonic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic,toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine,tryptophan, lysine and arginine. I

These or other salts of the new compounds, for example, the picrates,can be used also for purification of the bases obtained; the bases areconverted into salts, the salts are separated and the bases areliberated from the salts. In view of the close relationship between thefree compounds and the compounds in the form of their salts, whenever afree base is referred to in this context, a corresponding salt is alsointended, provided such is possible or appropriate under thecircumstances.

The invention further includes any variant of the pres ent process, inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components may be used in the form of their salts. Mainlythose starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being specially valuable.

The starting materials are known, or if they are new, may be prepared bymethods in themselves known. Those mentioned under items (a), (b) and(c) may be prepared as shown in J. Chem. Soc. 1951, 3464, Gaza. chim,ital. 84, 908 (1954) and Chem. Ber. 95, 2122 (1962). The startingmaterial mentioned under (d) can be obtained by reaction of a2-(1-alkenyl)-phenylmagnesium halide with an alkanal and, if desired,Oppenauer-oxidation of the tar-hydroxyalkyl compound obtained, andaddition of water or a hydrogen halide to the resulting 1-(l-alkenyl)-Z-(a-hydroxyor oxoalkyl)-benzene, the latter advantagenously in thepresence of peroxides. Hydroxy compounds so obtained may be esterified,for example, with the use of thionylhalides or sulfonic acid halides.Resulting l-(fl-haloalkyl)-2-(or-hydroxyalkyl)-benzenes or 1-(3-haloalkyl)-2-(a-hal0alkyl)-benzenes may be reacted with an arylaminoorarylcarbamyl-alkylamine, in order to obtain the compounds mentionedunder item (e).

Starting materials or final products that are mixtures of isomers may beseparated into simple isomers by methods in themselves known. Forexample, compounds that contain one or more asymmetrical carbon atomsmay be in the form of racemate mixtures, pure racemates or opticalantipodes. Mixtures of racemates, by virtue of the physicochemicaldifferences between the components, can be resolved into thestereoisomeric pure racemates (diestereoisomers), for example, bychromatography and/or fractional crystallization. Racemic products canlikewise be resolved into the optical antipodes, for example, byreaction with optically active acids, separation of the diastereomericsalts and liberation of the bases from the salts.

The compounds of the invention can be used in the free form or in theform of their salts, for example, for the manufacture or pharmaceuticaland feed preparations containing the said compounds in admixture withorganic or inorganic, solid or liquid pharmaceutical excipients suitableespecially for enteral, but also for parenteral administration. Suitableexcipients are substances that do not react with the new compounds, forexample, water, gelatine, lactose, starch, stearyl alcohol, magnesiumstearate, talc, vegetable oils, benzyl alcohols, gums, propyleneglycols, white petroleum jelly and other known medicinal excipients. Thepharmaceutical preparations may be, for example tablets, dragees orcapsules, or in liquid form as solutions, suspensions or emulsions. Theymay be sterilized and/ or contain adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure or buffers. They may further containother therapeutically valuable substances. The pharmaceuticalpreparation are prepared by conventional methods and contain about 0.1to 75%, more particularly 1 to 50%, of the active ingredient.

The following examples illustrate the invention; temperatures are givenin centigrade and all parts wherever given are parts by weight.

Example 1 To the solution of 12.6 g. 1-methyl-3,4-dihydro-isoquinolinein 30 ml. acetone the solution of 14.6 g. N-phenylchloracetamide in 70ml. acetone is added and the mixture refluxed for /2 hour. It is thenevaporated in vacuo and the residue recrystallized from isopropanol toyield some unreacted N-phenylchloracetamide which is discarded. Themother liquor is concentrated, the residue dissolved in hot water, thesolution filtered and to the filtrate an aqueous solution of potassiumiodide is added. The precipitate formed is filtered off, recrystallizedfrom ethanol to yield the 1-methyl-2-(N-phenylcarbamyl-methyl)-3,4-dihydro-isoquinolinium iodide of the formula melting at 227230.

The starting material is prepared as follows: 15.0 g.1-methyl-3,4-dihydro-isoquinoline hydrochloride are dissolved in 30 ml.water, the solution neutralized with sodium carbonate and extracted with100 ml. diethyl ether. The extract is dried, filtered and evaporated toyield the corresponding free base.

Example 2 To the hot solution of 1.0 g.1-methyl-2-(N-phenylcarbamyl-methyl)-3,4-dihydro-isoquinolinium iodidein ml. methanol 0.4 g. sodium borohydride are added in portions and thereaction mixture is allowed to stand at room temperature for one hour.It is then concentrated in vacuo, to the residue 20 ml. diethyl etherand 5 ml. water are added, the ethereal solution separated, dried,filtered and the filtrate acidified with a solution of hydrogen chloridein ethyl acetate. The precipitate formed is filtered off and dried. 0.7g. thereof are dissolved in water, the solution neutralized withpotassium carbonate, extracted with diethyl ether, the extract dried,filtered and evaporated.

The residual base is taken up in diethyl ether, the solution acidifiedwith hydrogen chloride in ethyl acetate, the precipitate filtered offand recrystallized from isopropanolacetone to yield the1-methyl-2-(N-phenylcarbamyl-methyl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride of the formula melting at 184-187".

8.0 g. l-methyl-Z-(N-phenylcarbamyl-methyl)-l,2,3,4-tetrahydro-isoquinoline are dissolved in 50 ml. diethyl ether and thesolution added dropwise to the stirred suspension of 3.42 g. lithiumaluminum hydride in 150 ml. diethyl ether. The mixture is stirred atroom temperature for 16 hours; hereupon 5.12 ml. ethyl acetate, 16 ml.water, 3.42 ml. 15% aqueous sodium hydroxide and 5.12 ml. water areadded in this order and the whole is filtered. The filtrate is dried,evaporated in vacuo, the residue dissolved in ml. diethyl ether and thesolution acidified with hydrogen chloride in ethyl acetate. Theprecipitate formed is filtered off and recrystallized from ethanol toyield the1-methyl-2-(Z-phenylamino-ethyl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride of the formula II-I melting at 235237.

Example 4 I CaH .HC1 CH Analysis.-Theory: C=66.9 l H=7.75 N:

7.42%. Found: 'C=66.76%, H=8.09%, N=7.40%.

Example 5 Preparation of 20,000 tablets each containing 0.4 g. of theactive ingredient.

Material: G.

l-methyl-2-(N-phenylcarbamyl-methyl) 3,4-

dihydro-isoquinolinium iodide 4,000 Gelatine 300 Corn starch (anhydrous)3,318 Talcum 1,250 Stearic acid 132 Purified water, q.s.

Pr0cedure.-The iodide and 1,452 g. of the starch are passed through a 16mesh screen and mixed thoroughly. The gelatine is dissolved in 2,000 ml.water, the solution combined with a suspension of 616 g. starch in 400ml. cold water and the whole heated on a water bath until a paste isformed. It is combined with the sieved powders using additional water,if necessary. The granulate is passed through a mesh screen, dried at 49and broken on a 9 mesh sceren in the Fitzpatrick mill, knives forward.The granules are mixed with the talcum, stearic acid and the remainingstarch and the mixture compressed into tablets using standard concavepunches scored and monogrammed.

Example 6 The compounds of the invention are useful in the veterinaryfield, for example, in the form of pharmaceutical preparations,feedstuffs or additives to the feed or drinking water.

Feedstuff additive containing of the active in gredient.

1-methyl-2-( N phenylcarbamyl-methyl) 3,4 dihydro-isoquinolinium iodide100 Medicinal carbon 100 Glucose 800 The thoroughly mixed additive isincorporated in the feed concerned, in an amount such as to achieve aconcentration therein of about 0.1 to 50 g., preferably about 1 g. perton of the feed.

Example 7 To the solution of 9.0 g. 1-methyl-3,4-dihydro-isoquinoline in45 ml. acetone and 5 ml. benzene, 15.0 g.N-(2,4,6-trichloro-phenyl)-chloroacetamide are added in small portionsand the mixture is refluxed for 3 /2 hours. It is evaporated, theresidue triturated with benzene, filtered off and recrystallized fromchloroform to yield the 1-methyl-2-[N-2,4,6-trichlorophenyl)-carbamylmethyl]- 3,4-dihydro-isoquinolinium chloride of the formula iELCm-QONHQQ 01 3 melting at 252253 with decomposition.

The starting material is prepared as follows: To the solution of 39.2 g.2,4,6-trichloro-aniline in 200 ml. toluone, the solution of 8.1 ml.chloroacetyl chloride in ml. toluene is added dropwise at roomtemperature while stirring. The resulting mixture is then diluted withml. toluene and stirred overnight at room temperature. It is filtered,the residue washed with some cold benzene and recrystallized frombenzene to yield the N-(2,4,6-trichloro-phenyl)-ch1oroacetamide meltingat -181".

I claim:

1. A compound of the formula l CH References Cited UNITED STATES PATENTS2,344,095 3/1944 Kulz 260-287 2,778,834 1/1957 Bruce et a1. 2602872,806,850 9/1957 Cavallito et al 260286 2,813,872 11/1957 Schmutz 2602862,830,049 4/1958 Biel 260288 X 2,951,013 8/1960 Dengel 260288 X DONALDG. DAUS, Primary Examiner US. Cl. X.R.

